Preventable adverse events, including nosocomial infections (NIS) and medication errors (MEs), are among the nation's most pervasive patient safety problems. Establishing effective reporting systems capable of compiling useful information on these events is a necessary but insufficient condition for improving outcomes. Creating the capacity for sustainable change requires region-wide exploration and evaluation of the multiple interrelated systems that transform that information into knowledge and learning. The Pittsburgh Regional Healthcare Initiative (PRHI) was created in 1997 in an effort to achieve the world's best patient outcomes by identifying and solving systemic problems at the point of patient care, including the elimination of NIS and MEs. PRHI is a collaboration of leaders from all major healthcare stakeholder groups in a six-county metro region representing diverse patient populations. Through close collaboration with US Pharmacopeia and the Center for Disease Control, our 30-hospital system is implementing MedMARx and components of the National Nosocomial Infection Surveillance System (NNIS). All healthcare facilities participating in this research demonstration have agreed to share their data locally, thus providing an important opportunity for cross-organizational comparisons. Based on shared analysis of regional outcomes data, prevention strategies and interventions are being developed for both NIs and MEs. These will be implemented through a variety of mechanisms including PRHI's existing Center for Shared Learning. Using multiple metrics we will explore three sets of study aims: 1) To understand how well the Reporting Systems associated with NIS and Mes succeed in creating usable information; 2) To understand how well the Feedback Review Systems function; and 3) To understand the Problem-Solving Systems through which knowledge is translated into organizational learning. Our evaluation will be aided by an investigative Data Coordinating Center and a comprehensive communications strategy. This unique collaboration may provide a generalizable model for regional, systems-based approaches to patient safety.